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Neuroendocrine Cancer Syndromes – Early Signs of a Late Diagnosis

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Diagnostic Challenges in NET Cancer (type Carcinoid).  Inner segments are the key symptoms, outer segments are some of the potential misdiagnosis/delayed diagnosis. Graphic courtesy of Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128: 1717-1751

One of the curious things about Neuroendocrine Cancer (NET Cancer) is that it can exhibit one or more vague symptoms collectively known as a ‘syndrome’.  Syndrome is an apt word to describe these complications as the most general meaning in medical terms is “group of symptoms that together are characteristic of a specific disorder or disease”

Most people think of Carcinoid Syndrome when they discuss NET Cancer but there are in actual fact, several associated syndromes depending on the location and type of NET Cancer. Not everyone will have a ‘syndrome’ in addition to their tumours. Take the most common form of NET Cancer as an example – statistics vary from source to source but it is estimated that around a 30-45% of all ‘midgut’ patients will present with metastatic disease and around a third of those (∼10-15% of all midgut) will exhibit Carcinoid Syndrome indicating their tumours are functional (secreting excess hormones, particularly serotonin).  It follows that Carcinoid Syndrome itself is not that common and it could be the same with other types of NET Cancer (even though it can appear more prevalent on forums). In fact a large proportion of Pancreatic NETs are non-functional at diagnosis.

These tumours and associated syndromes are treatable for most but the difficult part can be arriving at a diagnosis. Moreover, without a syndrome, some of these tumours can be silently growing and as they grow slowly, the ‘silence’ can go on for some years. Even with a syndrome, the root cause can remain disguised as the symptoms are similar to many day-to-day illnesses, again the reason for the title of this blog. Curiously, the lack of a syndrome can sometimes lead to an even later presentation and the consequences that arise (i.e. no signs to aid a diagnosis). There can be the odd exception but in general terms, NETs are either functional (with a syndrome) or non-functional (no syndrome).

The ISI Book on Neuroendocrine Tumors 2016 (Woltering et al) confirms there are a number of syndromes associated directly and indirectly with NET Cancer. For example Carcinoid, Gastrinoma, Insulinoma, Somatostatinoma, Glucagonoma, and VIPoma are described as individual syndromes according to their secretory hormones and peptides. The referenced publication expands on this list to aid diagnoses by including common presentations, associated tumour types and locations and the offending secreting hormones. You can see why NET Cancer is a diagnostic challenge!

Major NET Syndromes  – (information mainly taken from the ISI Book on NETs):

Carcinoid – a syndrome connected with conventional carcinoid locations (small intestine, lung, stomach, appendix etc).  Type 2 Gastric NET can be associated with Zollinger-Ellinson Syndrome (ZES) see also below.

Insulin – Insulinoma (Whipple’s Triad) – Whipple’s Triad is the classic description of insulinoma which includes symptoms of hypoglycemia with a low blood glucose concentration relieved by the ingestion of glucose. These tumours can be located anywhere within the pancreas in the cells that make insulin. Insulin is a hormone that controls the amount of  glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. Some of these tumours will be associated with MEN1.

Gastrin – Gastrinoma  A tumour that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers and diarrhea are caused by a tumour that makes gastrin, it is called Zollinger-Ellinson Syndrome (see also below).  Gastrinoma usually forms in the head of the pancreas. Some of these tumours may be associated with MEN1 syndrome.

GlucagonGlucagonoma.  A tumour that forms in cells that make make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas.  Some of these tumours may be associated with MEN1 syndrome.  See also Sweet’s Syndrome below.

Pancreatic Polypeptide (PP)PPoma.  A complicated one and not too much information (even in the ISI book). However, it’s the third most common type of islet cell tumour (i.e. pNET).  The function of pancreatic polypeptide is not completely understood. Patients present with weight loss, jaundice, and abdominal pain. The diagnosis is confirmed by pancreatic polypeptide levels > 300 pg/ml. Some of these tumours may be associated with MEN1 syndrome.

VIPoma. Sometimes the syndrome is referred as WDHA – Watery Diarrhea, Hypokalemia (potassium deficiency), and Achlorhydria (absence of hydrochloric acid in gastric secretions).  VIPomas make vasoactive intestinal peptide (VIP). VIPoma may also be called Verner-Morrison syndrome.

SomatostatinSomatostatinoma is a very rare NET, with an incidence of one in 40 million persons. These tumours arise from the delta cells in the pancreas, although these cells can also be present in duodenal tissue where around 40% of these tumours occur. Somatostatin is a naturally occurring peptide that inhibits the function of almost all gut hormones (author’s note – this should give you an appreciation of how somatostatin analogues tackle associated syndromes but gives you certain side effects as a result!)

Hedinger Syndrome – the technical term for Carcinoid Heart Disease.

MEN1 – Mainly involved the 3 Ps, Pituitary, Pancreas and Parathyroid.  The pituitary tumours are primarily Prolactinomas, the pancreatic tumours are mainly PPomas, Gastrinomas and Insulinoma.  Many also have association with Zollinger-Ellinson  syndrome (ZES). Read more here.  Previously known as Wermer Syndrome.

MEN2 (A & B) – including association with Medullary Thyroid Cancer (MTC) (including the familial type FMTC) and Pheochromocytoma/Paraganglioma and  Parathyroid hyperplasia.  Read more here.

Von Hippel-Lindau (VHL) – not an exclusively NET syndrome. VHL is a rare disorder caused by a faulty gene. It is named after the two doctors who first described the disease, and affects about one in 35,000 people. Tumours develop in one or more parts of the body. Many of these tumours involve the abnormal growth of blood vessels in parts of the body which are particularly rich in blood vessels. Areas most frequently affected are the eyes, the back of the brain (cerebellum), the spinal cord, the kidneys, the adrenal glands and the pancreas. People are affected differently, even within the same family. The only VHL tumour which tends to run in families affects the adrenal glands (Pheochromocytoma).
Different VHL features tend to develop at different ages. The eye angiomas often develop in childhood. Others, including tumours found in the cerebellum, spinal cord or adrenal glands (Haemangioblastomas and Pheochromocytomas) can develop from late childhood onwards. The kidney tumours are usually the last things that develop, from the mid-twenties onwards.  Most VHL related tumours are benign,

Zollinger-Ellinson Syndrome (ZES).  This is a rare condition in which one or more tumours form in the pancreas, the upper part of the duodenum or the stomach.  These tumours secrete large amounts of the hormone gastrin, which causes your stomach to produce too much acid. The excess acid can lead to peptic ulcers, in addition to diarrhea and other symptoms.  Associated with Gastrinoma (pNET) and Type 2 Gastric NETs.

Cushing’s – also known as hypercortisolism.  A collection of symptoms caused by very high levels of a hormone called cortisol in the bodyAssociated with AdrenoCorticoTropic Hormone (ACTH).  In Cushing’s disease, oversecretion of pituitary ACTH induces bilateral adrenal hyperplasia. This results in excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone. Cushing’s disease, a subset of Cushing’s syndrome, is due to a pituitary corticotroph adenoma and results in a partial resistance to the suppression of ACTH by cortisol so that secretion is unrestrained. In contrast, causes of Cushing’s syndrome may include the following:

•   Adrenal adenoma or carcinoma arise spontaneously. ACTH levels are undetectable.

•   Non-pituitary (ectopic) tumours produce ACTH. They most frequently originate in the thorax and are highly aggressive small cell carcinomas of the lung or slow- growing bronchial or thymic carcinoid tumours. Some produce corticotropin- releasing hormone (CRH) instead, which stimulates pituitary ACTH secretion and can therefore mimic a pituitary tumour.

•   Other causes include carcinoid tumours of the gastric, pancreatic, and intestinal organs; Pheochromocytomas, and MCT.

The hallmark of Cushing’s syndrome is that ACTH levels are partially resistant to suppression with dexamethasone, even at very high doses.  Some MEN patients with pituitary tumours may have Cushing’s Syndrome.

Sweet’s – Dermatitis/rash associated with Glucagonomas.  Not to be confused with Pellagra.

There are many other less known syndromes that appear to be directly or indirectly connected with Neuroendocrine Tumours and I may update this blog if I discover they are more prevalent than I think.

As for my own experience of syndromes, I did once show symptoms of the most common NET syndrome (currently known as Carcinoid syndrome) where the key symptoms are flushing, diarrhea and wheezing.  You can see why those symptoms are frequently and easily confused with other conditions. If you have a similar diagnosis, you may benefit from looking at something known as The 5 E’s which is a useful list of things to be wary of.

I’m certain that I’m now ‘syndrome free’ but I did suffer for a year in 2010 leading up to diagnosis and until my treatment was underway.  I was experiencing flushing and infrequent bouts of diarrhea but I totally ignored it (well, I am a man!). However, it ended up being instrumental in my diagnosis albeit some good luck was involved in getting to that point.  My twist of fate which involved a low hemoglobin score led me to a scan and ‘bingo’.  I had a ‘gastrointestinal blip’ some 18 months previously but that proved colonoscopy negative.  When I read about the experiences of other people who suffer much worse than I ever did, I know I got off lightly despite my distant and metastatic tumour disposition and seemingly late diagnosis.  However, my treatment played and continues to play its part.

For many, the vague and routine symptoms generated by a syndrome contribute to the fact that NET Cancer is frequently misdiagnosed with some people suffering from the side effects for many years before a correct diagnosis is made.

Neuroendocrine Cancer – shh! Can you hear it? 

Thanks for reading

Ronny

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9 Comments

  1. Deanna Vickery, Mrs says:

    Thankyou for this. the diagram is very interesting. I had late-diagnosed Cushings; the uncontrollable weight went on in the early ’80s. When I started having problems with my balance/vision in ’98 my Dr sent me for head MRI. Even this was misiagnosed by an ‘expert’ as Multiple Sclerosis and he took me into hospital to put me on a week of IV cortisol! I was saved by his Registrar who carefully read all my notes which showed abnormally high levels of cortisol, sent me for another MRI and correctly diagnosed a pituitary adenoma. This was removed in ’99 and after a year my weight went back to 9stone (from @ 13stone). Life got back to normal. Until 2011 when I suddenly had bouts of excruciating mid-gut pain about an hour after eating. To cut a long story short a midgut tumour was removed in Nov. 2011 along with a 60% liver resection due to metastisis.
    I never had any NET symptoms/syndrome until after the operations and new metastisis showed-up in a 2013 scan. That’s when I was put on 90mg monthly Lanreotide injections.
    But My symptoms are still not stable and I suffer with a mimick of IBS. My diet has been pruned as much as it can be. One day I’m ok, the next i have diaorrhea. It is a very isolating disease in that it’s so unpredictable. Gone are the days of eating out with friends/family.
    I’ve adjusted, but it’s a very lonely life….

    I really enjoy your blogs as they ‘understand’ – because, of course, you yourself are a sufferer.
    Grateful thanks,
    Dee Vickery

    Liked by 1 person

  2. Karen Long says:

    Would you mind emailing me a copy of the chart as well. I wish many physicians had a copy of this chart. Thank you – for this and all that you do.

    Liked by 1 person

  3. kimkmattke says:

    Im having my brain scans this morning and after yesterday’s results Dave and I have a guy feeling how these scans will turn out.. We have driven 240 miles and not one word!

    Liked by 1 person

  4. Marion Shead says:

    I wanted to copy the chart at the top, the one in different shades of blue, as I had many of those things before I was diagnosed. I still have many But it won’t copy. Any suggestions?

    Liked by 1 person

  5. cy says:

    Well Done! The same E’s do not apply to everyone. We each must find out what the culprits are in our syndrome. This disease is so frustrating!

    Liked by 1 person

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